HU195806B - Process for producing new piperazinyl-benzisothiazol- and piperazinyl-benzisoxasol-derivatives - Google Patents
Process for producing new piperazinyl-benzisothiazol- and piperazinyl-benzisoxasol-derivatives Download PDFInfo
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- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
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- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
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- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
Description
A találmány tárgya eljárás piperazinil-benzizotiazol- vagy piperazinil-benzoizoxazol származékok és savaddíciós sóik előállítására.The present invention relates to a process for the preparation of piperazinyl benzisothiazole or piperazinyl benzoisoxazole derivatives and their acid addition salts.
A 190.997 lajstromszámú magyar szabadalmi leírás olyan (I) általános képletű vegyületeket ismertet, aholHungarian Patent Publication No. 190,997 discloses compounds of formula I wherein
R jelentése (a), (b), (c), (d), (e) vagy (f) általános képletű csoport, ahol n jelentése 3 vagy 4, Rj és R2 jelentése egymástól függetlenül rövidszénláncú, 1-4 szénatomot tartalmazó alkilcsoport,R is a radical of formula (a), (b), (c), (d), (e) or (f) wherein n is 3 or 4; R1 and R2 are each independently lower alkyl having from 1 to 4 carbon atoms. .
Y jelentése oxigénatom vagy kénatom, és jelentése hidrogénatom vagy halogénatom.Y is oxygen or sulfur, and is hydrogen or halogen.
A találmány szerinti vegyületek üj közbenső termékek az (I) általános képletű vegyületek előállításánál.The compounds of the invention are new intermediates for the preparation of compounds of formula (I).
A jelen találmány szerinti intermedierek (III) általános képletű vagy (IV) képletű vegyületek. A (III, általános képletbenThe intermediates of the present invention are compounds of Formula III or Formula IV. In the formula (III)
Y jelentése oxigénatom vagy kénatom.Y is oxygen or sulfur.
A találmány szerinti píperazinil-benzizotiazol- ós benzizoxazol-származékokat úgy állítjuk elő, hogy valamely (II) általános képletű 3-klór-l,2-benzizotiazolt vagy 3-klór-1,2-benzizoxazolt vagy (Ila) képletű 3-klór-2,1-benzizotiazolt emelt hőmérsékleten fölöslegben vett piperazinnal reagáltatunk. A kiindulási 3-klór-l,2-benzizotiazolt például úgy állítjuk elő, hogy l,2-benzizotiazol-3(2H)-ont 4 órán át 100-140 ’C hőmérsékleten, foszforpentakloriddal reagáltatunk. Hasonló módon, az l,2-benzizoxazol-3-ont H. Boshagen (Bér. 100, 3326 (1967)) módszere szerint, foszforoxikloriddal és trietilaminnal kezelve alakítjuk át 3-klór-l,2-benzizoxazollá.The piperazinyl benzisothiazole benzisoxazole derivatives of the invention are prepared by reacting a 3-chloro-1,2-benzisothiazole of formula II or 3-chloro-1,2-benzisoxazole or a 3-chloro compound of formula IIa. 2,1-Benzisothiazole is reacted with excess piperazine at elevated temperature. For example, the starting 3-chloro-1,2-benzisothiazole is prepared by reacting 1,2-benzisothiazol-3 (2H) -one with phosphorus pentachloride at 100-140 ° C for 4 hours. Similarly, 1,2-benzisoxazol-3-one is converted to 3-chloro-1,2-benzisoxazole by treatment with phosphorus oxychloride and triethylamine according to the method of H. Boshagen (Bér. 100, 3326 (1967)).
A találmány szerinti eljárást a továbbiakban - a találmány oltalmi körének szűkítése nélkül - példákkal szemléltetjük.The invention is further illustrated by the following non-limiting examples.
I. PéldaExample I
3-(Piperazin-I-iI)-l,2-benzizotiazo)3- (piperazin-l-yl) -l, 2-benzisothiazole)
37,8 g (0,235 mól) 3-klór-l,2-benzizotiazol ée 304,2 g (3,53 mól) piperazin elegyét argon atmoszférában, 20 órán át 120 ’C hőmérsékleten tartjuk egy zárt edényben. Utána az elegyel feloldjuk 2 1 vízben, és a vizes oldatot diklór-metánnal többször kirázzuk. A diklór-metános oldatokat egyesítjük, magnézium-szulfáton megszárítjuk, és az oldószert csökkentett nyomáson ledesztilláljuk. A maradékot feloldjuk dietil-éterben, az 0)datlan részeket kiszűrjük, majd az oldószert csökkentett nyomáson ledesztilláljuk. Ily módon viszkózus olaj formájában 24,4 g (hozam: 47 %) 3-(piperazin-l-il)-l,2-benzizotiazol szabad bázist kapunk.A mixture of 37.8 g (0.235 mol) of 3-chloro-1,2-benzisothiazole and 304.2 g (3.53 mol) of piperazine was kept under argon at 120 ° C for 20 hours in a closed vessel. The mixture was then dissolved in 2 L of water and the aqueous solution was extracted several times with dichloromethane. The dichloromethane solutions were combined, dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was dissolved in diethyl ether, the non-volatiles were filtered off and the solvent was distilled off under reduced pressure. This gave 24.4 g (47%) of 3- (piperazin-1-yl) -1,2-benzisothiazole free base as a viscous oil.
A szabad bázis egy mintáját úgy alakítjuk sósavas sóvá, hogy dietil-éterben etanolos sÓBav-oldattal kezeljük, majd a sót metanol és etanol elegyéből átkristályositjuk. Ily módon analitikailag tiszta 3-(piperazin-l-iD-1,2-benzizotiazol-hidrokloridot kapunk, op.: 280 “C (bomlik).A sample of the free base was converted to the hydrochloric acid salt by treatment with ethanolic salt salt in diethyl ether and recrystallized from a mixture of methanol and ethanol. This gave 3- (piperazine-1D-1,2-benzisothiazole hydrochloride), analytically pure, m.p. 280 DEG C. (dec.).
Analízis a C11H13N3S.HCI képlet alapján:Analysis calculated for C11H13N3S.HCI:
számított: C: 51,66; H: 5,52; N: 16,43 %; talált: C: 51,34; II: 5,46; N: 16,16 %.Calculated: C, 51.66; H, 5.52; N, 16.43. Found: C, 51.34; II: 5.46; N: 16.16%.
2. PéldaExample 2
3-(Piperazin-1-)1)-1,2-benzizöxs zol3- (Piperazine-1-) -1) -1,2-benzisoxazole
19,6 g (0,128 mól) 3-klór-l,2-benzjzoxazol és 110 g (1,28 mól) piperazin elegyet zárt edényben, 20 órán ót 120 ’C hőmérsékleten ta-tjuk. Utána az elegyet vizzel hígítjuk, és a vizes oldatot diklór-metánnal többször kirázzuk. A diklór-metános részeket egyesítjük, magnézium-szulfáton megszárítjuk, ée az oldószert csökkentett nyomáson ledesztilláljuk. Ily módon 21,2 g (hozam: 82 %) 3-(pipera.,in-l-íl)~] ,2-benzizoxazol szabad bázist kapunk.A mixture of 3-chloro-1,2-benzoxoxazole (19.6 g, 0.128 mol) and piperazine (110 g, 1.28 mol) was kept in a sealed vessel for 20 hours at 120 ° C. The mixture was diluted with water and the aqueous solution was extracted several times with dichloromethane. The dichloromethane fractions were combined, dried over magnesium sulfate and the solvent was distilled off under reduced pressure. This gave 21.2 g (82%) of 3- (piperazin, in-1-yl) -1,2-benzisoxazole free base.
A szabad bázis egy mintáját sósavas sóvá alakítjuk, és a sót metanol és etanol elegyéböl átkristályoBÍtjuk. Ily módon analítikailag tiszta 3-(piperazin-l-il)-l,2-benzizoxazol-hidrokloridot kapunk, op.: 326 “C (bomlik).A sample of the free base was converted to the hydrochloric acid salt and recrystallized from a mixture of methanol and ethanol. This gave analytically pure 3- (piperazin-1-yl) -1,2-benzisoxazole hydrochloride, m.p. 326 ° C (dec.).
Analízis a CnHnNsO.NCl képlet alapján:Analysis based on the formula CnHnNsO.NCl:
számított: C: 55,12; H: 5,89; N: 17,54 %; talált: C: 55,25; H: 5,82; N: 17,53 %.Calculated: C, 55.12; H, 5.89; N: 17.54%; Found: C, 55.25; H, 5.82; N: 17.53%.
3. PéldaExample 3
8- {4-(4-(1,2-ben zizotiazol-3-il)-plperazin-l~ill-bi}til)-8-azaepiro[4,5] dekán-7,9-dion (a találmány szerinti intermedierek felhasználása: referencia példa).8- {4- (4- (1,2-Benzisothiazol-3-yl) -piperazin-1-yl-bi} ethyl) -8-azaepiro [4,5] decane-7,9-dione (the invention) (use of intermediates according to Reference Example).
A) módszerMethod A)
24,3 g (0,11 mól) 3-<piperazin-l-il)-l,2-benzizotiazol, 33,5 g (0,11 mól) 8-(4-bróm-butil)-8-azaspiro-[4,5) dekán-7,9-dion,3- (piperazin-1-yl) -1,2-benzisothiazole (24.3 g, 0.11 mol), 8- (4-bromobutyl) -8-azaspiro- (33.5 g, 0.11 mol). [4,5] decane-7,9-dione,
32,4 g (0,23 mól) vízmentes kálium-karbonát és 3,9 g (0,023 mól) kálium-jodid 1 1 acetonitr llel készült elegyét 20 órán át keverés közben forraljuk. Utána az oldatlan részeket kiszűrjük, a szűrletröl az oldószert csökkentett nyomáson ledesztilláljuk és a maradékot feloldjuk 350 ml kloroformban. Az oldatlan részeket kiszűrjük, és a szűrletröl az oldószert csökkentett nyomáson ledesztilláljuk. A maradékot dietil-éterrel eldörzsöljük, behütjük és n kivált szilárd anyagot kiszűrjük. Ezt a szilárd terméket acetonitrilből, csontBzéniel derítve átkristályositjuk. Ily módon első generációként 25,1 g (op.: 120-124 ’C), második generációként 6,0 g (op.: 123-126 °C) cím szerinti vegyület szabad bázist kapunk, tehát az ŐBszhozam 31,1 g (64 %). B terméket acetonitrilből átkristályosítva analitikáikig tisztu 8-(4-( l,2-beozizotiazol-3-il)-2D piperazin-l-ill-butil)-8-aza-spiro[ 4,5 ] dekán-7,9-diont kapunk, op.: 124-126 ’C.A mixture of 32.4 g (0.23 mol) of anhydrous potassium carbonate and 3.9 g (0.023 mol) of potassium iodide in 1 L of acetonitrile is heated to reflux for 20 hours. The insolubles were filtered off, the filtrate was evaporated under reduced pressure and the residue was dissolved in 350 ml of chloroform. The insolubles were filtered off and the filtrate was evaporated under reduced pressure. The residue was triturated with diethyl ether, cooled and the solid separated by filtration. This solid product is recrystallized from acetonitrile, triturated with bone Benesene. In this way, the first generation of the free base of the title compound was 25.1 g (m.p. 120-124 ° C) and the second generation 6.0 g (m.p. 123-126 ° C) of 31.1 g (m.p. 64%). Product B is recrystallized from acetonitrile to afford analytical grade 8- (4- (1,2-beozisothiazol-3-yl) -2D-piperazin-1-yl-butyl) -8-aza-spiro [4,5] decane-7,9-dione. 124-126 ° C.
Analízis a CnHaaNíChS képlet alapján:Analysis by CnHaaNiChS:
számított: C: 65,42; H: 7,32; N: 12,72 talált: C: 65,45; H: 7,31; N: 12,75 %.Calculated: C, 65.42; H, 7.32; N, 12.72 Found: C, 65.45; H, 7.31; N: 12.75%.
NMR-spektrum (CDCIj): 1,60 (12Hm),· 2,57 (4H, s), 2,62 (611, m), 3,54 (4H, m), 3,79 (2H, m), 7,34 (2H, ra), 7,81 (2H, m).Nuclear Magnetic Resonance Spectrum (CDCl3): 1.60 (12Hm), 2.57 (4H, s), 2.62 (611, m), 3.54 (4H, m), 3.79 (2H, m) , 7.34 (2H, m), 7.81 (2H, m).
g szabad bázis forró izopropanollal kéezült azuazpenziójóhoz hozzáadunk 12,3 ml 5,7 normál etanoloe sósav-oldatot, az így kapott oldatot lehűtjük, a kivált csapadékot kiszűrjük és csökkentett nyomóson, 80 ’C hőmérsékleten megszárítjuk. Ily módon 29,6 g 8-(4-(4-( 1,2-benzizo tiazol-3-il)-piperazin-1-il)-butil}-8-aza-spiro[4,5]dekán-7,9-dién-hidrokloridot kapunk, op: 219-220 ’C.To a suspension of the free base in hot isopropanol (g) is added 12.3 ml of a 5.7N hydrochloric acid solution in ethanol (5.7 ml), the solution is cooled, the precipitate is filtered off and dried under reduced pressure at 80 ° C. 29.6 g of 8- (4- (4- (1,2-benzisothiazol-3-yl) piperazin-1-yl) butyl} -8-aza-spiro [4,5] decane-7) are thus obtained. 9-diene hydrochloride, m.p. 219-220 ° C.
Analízis a ChHjíNíOjS.HCI képlet alapján:Analysis based on the formula ChHjíNíOjS.HCI:
számítolt: C: 60,43; H: 6,98; N: 11,75 %; talált: C: 60,57; H: 6,98; N: 11,75 %.Calculated: C, 60.43; H, 6.98; N: 11.75%; Found: C, 60.57; H, 6.98; N: 11.75%.
NMR-spektrum (DMSO-de): 1,55 {12H, m),Nuclear Magnetic Resonance Spectrum (DMSO-d6): 1.55 (12H, m),
2,64 (4H, s), 3,40 (10H, m), 4,05 (2H, d, 12 OHz), 7,00 (2H,m), 8,10 (2H, m), 12,15 (IH, széles s).2.64 (4H, s), 3.40 (10H, m), 4.05 (2H, d, 12 Hz), 7.00 (2H, m), 8.10 (2H, m), 12, 15 (1H, bs).
A Bzabad bázis egy mintáját etanolos sósav-oldatot tartalmazó acetonitrilből kristályosítva 8-(4-[4-(l,2-benzizotiazol-3-il)-piperazin-l-Íl]-butil}-8-azas-piro[4,5]dekán-7,9-dion-dihidroklorid-dihidrátot kapunk: op.: 118-120 ’C.A sample of the Bzabad base was crystallized from acetonitrile containing ethanolic hydrochloric acid solution 8- (4- [4- (1,2-benzisothiazol-3-yl) piperazin-1-yl] butyl} -8-azaspiro [4 5] decane-7,9-dione dihydrochloride dihydrate, m.p. 118-120 ° C.
Analízis a C2«H3íN4O2S'2HC1.2H2O képlet alapján:Analysis based on the formula C2H3N4O2S'2HC1.2H2O:
számított: C: 52,45; H: 6,97; N: 10,20 %; talált: C: 52,68; H: 6,91; N: 10,29 %.Calculated: C, 52.45; H, 6.97; N: 10.20%; Found: C, 52.68; H, 6.91; N, 10.29%.
NMR-spektrum (DMSO-de): 1,55 (12H, m),Nuclear Magnetic Resonance Spectrum (DMSO-d6): 1.55 (12H, m),
2,64 (4H, s), 3,14 (4H, m), 3,58 (6H, m), 4,06 <2H, d, 12,OHz), 5,48 (4H, s), 7,50 (2H, m), 8,10 (2H, m), 11,60 (IH, széles s).2.64 (4H, s), 3.14 (4H, m), 3.58 (6H, m), 4.06 <2H, d, 12 Hz), 5.48 (4H, s), 7 , 50 (2H, m), 8.10 (2H, m), 11.60 (1H, broad s).
B) módezerModule B)
5,0 g (0,0228 mól) 3-(piperazin-l-il)-l,2-benzizotiazol, 9,8 g (0,0456 mól) 1,4-dibróm-butón és 7,9 g (0,057 mól) finoman elporitott, vízmentes kálium-karbonát 100 ml etanollal készült elegyét 16 órán át keverés közben forraljuk. Lehűtés utón az oldatlan részeket kiszűrjük, ée a szűrletröl az oldószert csökkentett nyomáson ledcsztilláljuk. A szilárd maradékot 70 ml izopropanollal felforraljuk, és az oldatlan részeket kiszűrjük. A szűrietet eredeti térfogatának körülbelül felére betÖményítjük, majd lehűtjük. Ily módon 5,58 g (hozam: 69,1 %) 8-l,2-henzizotiazol-3-il)-8-aza-5-azonÍa-Bpiro(4,5]dekón-bromidot kapunk, op.: 246,5-253 ’C.5.0 g (0.0228 mol) of 3- (piperazin-1-yl) -1,2-benzisothiazole, 9.8 g (0.0456 mol) of 1,4-dibromo-butone and 7.9 g (0.057) of mole) of finely pulverized, anhydrous potassium carbonate in 100 mL of ethanol is heated at reflux for 16 hours. After cooling, the insolubles were filtered off and the filtrate was distilled off under reduced pressure. The solid residue was boiled with isopropanol (70 mL) and the insolubles were filtered off. The filtrate was concentrated to about half its original volume and then cooled. Yield: 5.58 g (69.1%) of 8-1,2-benzisothiazol-3-yl) -8-aza-5-aza-Biro [4,5] decone bromide, m.p. 246 , 5-253'C.
Analízis a Ci5H2oBrN3S.l/4H20 képlet alapján: számított: C: 50,21; H: 5,76; N: 11,71;Analysis calculated for C 15 H 20 BrN 3 S · 1 / 4H 2 O: C, 50.21; H, 5.76; N: 11.71;
HxO: 1,26 %;H x O: 1.26%;
talált: C: 50,04; H: 5,68; N: 11,60;Found: C, 50.04; H, 5.68; N: 11.60;
H2O: 1,50 %.H2O: 1.50%.
2,52 g (0,0151 mól) 3,3-tetrametilén-glu-tárimid, 5,34 g (0,0151 mól) 8-(l,2-benzizoti-azol-3-il)-8-aza-5-azonia-spirol4,5]dekén-bromid és 2,4 g (0,0173 mól) porított kálium-karbonát 125 ml toluollal készült elegyét 24 órán ót keverve forraljuk, majd az oldatlan részeket kiszűrjük, és a ezürletről az oldószert ledesztillóljuk. A maradékot felvesszük forró toluolban, és forró heptánnal hígítjuk. A forró oldatot aktivszénnel kezeljük, a szenet kiszűrjük, majd lehűtjük/ Ily módon 4,46 g (hozam: 67,2 %) szilárd terméket kapunk, op.: 109,5-120 ’C.2.52 g (0.0151 mole) of 3,3-tetramethylene glutarimide, 5.34 g (0.0151 mole) of 8- (1,2-benzisothiazol-3-yl) -8-aza- A mixture of 5-azonia spirol4.5] decene bromide and 2.4 g (0.0173 moles) of powdered potassium carbonate in 125 ml of toluene was refluxed for 24 hours, the insolubles were filtered off and the solvent was distilled off from the filtrate. The residue was taken up in hot toluene and diluted with hot heptane. The hot solution is treated with activated carbon, the carbon is filtered off and cooled to give 4.46 g (67.2%) of a solid, m.p. 109.5-120 ° C.
E terméket metanolból átkristályositvaThis product was recrystallized from methanol
8-(4-[4-(4,5-benzjzotiazol-3-Íl)-piperazin-lil]-butil)-8-aza-spiro[4,5)-dekán-7,9-dion szabad bázist kapunk, op.: 127,5-130 ’C.8- (4- [4- (4,5-Benzothiazol-3-yl) piperazinyl) butyl) -8-aza-spiro [4,5] decane-7,9-dione is obtained as the free base. mp 127.5-130 ° C.
4. PéldaExample 4
5-(Piperazin-1-il)-2,1-benzizoiiazoi5- (piperazin-1-yl) -2,1-benzizoiiazoi
4,79 g (0,028 mól), Albert és munkatársai [J. Hét. Chem., 15, 529 (1978)] módszerével előállított 5-klór-2,l-benzizotiazol és 36,2 g (0,42 mól) piperazin elegyét zárt edényben 18 órán át 120 ’C hőmérsékleten tartjuk. Lehűtés után a reakcióelegyet feloldjuk 400 ml vízben, a vizes oldatot kirázzuk először dietil-éterrel, majd diklór-metánnal. Az egyesített szerves részeket magnézium-szulfáton megszárítjuk és az oldószert csökkentett nyomáson ledesztillóljuk. Ily módon szabad bázis formájában 5,67 g (hozam: 90 %) 5-(piperazin-l-il)-2,l-benzizotiazolt kapunk.4.79 g (0.028 mol), Albert et al., J. Med. Seven. Chem., 15, 529 (1978)] and a mixture of 5-chloro-2,1-benzisothiazole (36.2 g, 0.42 mol) and piperazine (18.2 g) were kept in a closed vessel at 120 ° C for 18 hours. After cooling, the reaction mixture was dissolved in water (400 mL), and the aqueous solution was partitioned between diethyl ether and dichloromethane. The combined organic layers were dried over magnesium sulfate and the solvent was distilled off under reduced pressure. This gave 5.67 g (90%) of 5- (piperazin-1-yl) -2,1-benzisothiazole as the free base.
A szabad bázis egy mintáját etanolos oldatban etanolos sósav-oldattal sósavas sóvá alakítjuk, ily módon analitikailag tiszta 5-(piperazin-I-il)-2,l-benzizotíazol-dihidrokloridol kapunk, op.: 274-276 ’C (bomlik).A sample of the free base was converted to the hydrochloride salt in ethanolic hydrochloric acid to give analytically pure 5- (piperazin-1-yl) -2,1-benzisothiazole dihydrochloridol, m.p. 274-276 ° C (decomposed).
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US06/333,830 US4411901A (en) | 1981-12-23 | 1981-12-23 | Benzisothiazole and benzisoxazole piperazine derivatives |
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HU86744A HU195806B (en) | 1981-12-23 | 1982-12-22 | Process for producing new piperazinyl-benzisothiazol- and piperazinyl-benzisoxasol-derivatives |
HU824132A HU190997B (en) | 1981-12-23 | 1982-12-22 | Process for preparing benzisothiazolyl-and benzisoxazolyl-piperazine derivatives |
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